11beta, 12beta-epoxypregnane-3, 20-dione



United States Patent ()fiice 3,075,969 1113,12fi-EPXYPREGNANE-3,20 DI0NEJosef E. Herz and Josef Fried, New Brunswick, N.J., as-

signors to Olin Mathicson Chemical Corporation, New York, N.Y., acorporation of Virginia No Drawing. Filed July 1, 1%5, Ser. No. 519,682

1 Claim. (Cl. 260-23955) This invention relates to the synthesis ofvaluable steroids; and has for its object the provision of (I) anadvantageous process of preparing steroidsof the pregnane (including theallopregnane, pregnene and pregnadiene) series having a Hot-halogensubstituent and an ll-keto or llfi-hydroxy substituent, and of (11)certain steroids useful themselves as physiologically active steroids orin the preparation of physiologically active steroid derivatives.

The process of this invention essentially comprises: (a) converting a A-steroid of the pregnene (including the allopregnene, pregnadiene andpregnatriene) series into the corresponding l2a-bromo-llfi-hydroxysteroid of the pregnane (including the allopregnane, pregnene, andpregnadiene) series; (b) converting the latter into the corresponding115,125-epoxy derivative thereof; (0) converting the 1lfi,12,3-epoxyderivative into the corresponding 12cc-h310-11fi-hYdIOXY derivativethereof (when the halo group is bromine, steps (b), and (c) can, ofcourse, be eliminated); (d) converting said 12a-halo-1lfl- 3,075,969Patented Jan. 29, 1%63 hydroxy derivative to the corresponding 4,8-bromo(or 2,4-dibromo) derivative, and thence by dehydrobromination to thecorresponding M-pregnene (or a mixture of the corresponding A-pregnadiene and A' -pregnadiene) derivative (if the initial A -steroidcontains the requisite 4,5- and/or 1,2;4,5- and 4,5;6,7-unsaturation,step (d) can, of course, be eliminated); and (e) optionally oxidizingthe llfl-hydroxy steroid, thus formed, to the corresponding ll-ketoderivative.

The compounds of this invention comprise: (A) the intermediate11,8,125-ep0xy steroids of the pregnane (including the. allopregnane,pregnene and pregnadiene) series; (B) the-intermediatel2ot-halo-llfi-hydroxy steroids of the pregnafie (including theallopregnane) series, wherein the halo radical is chlorine or fluorine(i.e. a halogen of atomic weight greater than 18 and less than 36); (C)the intermediate l2a-halo-4 3-bromo-l lfi-hydroxy steroids of thepregnane series; (D) the intermediate 12a-halo-2,4-dibromo-1lfi-hydroxysteroids of the pregnane (including the allopregnane) series; and (E)the physiologically active IZa-halo-l lfl-hydroxy (or 11-keto)-A-steroids of the pregnene (including the A- and A -pregnadiene) series.

For a clearer understanding of the foregoing general and followingdetailed description of the processes of this invention, reference ismade to the following schematic analysis:

and

wherein the 1,2; 4,5; and '6,7-positions are doubleibondjed orsaturated, and wherein individually R is hydrogen, R is hydroxy, ortogether R and R is x0 (keto) or a group convertible thereto byhydrolysis (e.g. gketal), R and R as keto being preferred, X is halogen[preferably a halogen of atomic weight greater than 1-8 and less than 36(Le. chlorine or fiuorine)], Y is hydrogen, hydroxy, or acyloxy, Z ishydrogen or m-hydroxy, and GBr is an N-bromarnide (including imide) of acarboxylic acid (including derivatives).

Compounds suitable as initial reactants in ;the process of thisinvention include preferably A -pregnene-3,20 diodes and A-pregnene-2l-ol-3,20-diones and esters thereof [particularly carboxylicacid esters such as hydrocarbon carboxylic acid esters having less thanten carbon atoms in the acid moiety, as exemplified by the loweralkanoic acid esters (e.g. the acetate, propionate, butyrgate, andenanthate) and the monocyclic hydrocarbon jaromatic carboxylic acidesters (e.g. the benzoate)], al-

though otherstarting materials may alsobeused, such as:

dione and esters thereof; A -pregnadiene-No el-3,20-

dione; A -pregnadiene-.17a,21-diol-3,2O-dione and esters thereof; A-pregnene 17oz ol-3,20-dione; AU-pregnene- -l7a,2l-diol-3,20-dione andesters thereof; A pregnatriene 3,20 dione; A-pregnatriene-17a-ol-3,20-dione; A -pregnatriene-21-ol-3,20-dione andesters thereof; d -pregnatriene 1701,21 diol-3,20-dione and estersthereof; A -pregnat1'iene-3,20-dione; A -pregnatriene-l7a-ol-3,20-dione;A -pregnatriene :21 ol 3,20- dione and esters thereof; and Apregnatrinc-170:,21- diol-3,20-dione and esters thereof.

These compounds are reacted with a compound .pf the formula 631-,wherein GBr is as above-defined, and is preferably an N-bromamidc of alower allganoic acid (e.g. N-bromacetamide), an N-bromamide of a loweralkendioic acid (e.g. N-br'omosuccinimide), or dibromodimethylhydantoin.This reaction is optimally carr-ied out in the presence of a strong acid(e.g. perchloric acid) whereby the desired brominated product is formedto the exclusion of undesired by-products.

The reaction results in the production of Compounds A (preferablywholly-saturated and of cis'configuratio'n in the -position), which arethen reacted with a basic reagent, such as an alkali metal salt of aweak organic acid (e.g. an alkali metal acetate or carbonate) or an 75Compounds G.

alkali metal hydroxide (e.g. potassium hydroxide), in a suitable solventsuch as alcohols, lower alkanoic acids, or

ketones (preferably in an alkanol such as methanol or ethanol) to formthe 115,12p3-epoxy derivatives of this invention, Compounds B.

pounds A are re-forrned; otherwise, new steroid derivatives having aIZu-halo and 11B- hydroxy substituent are obtained.

If the initial reactant or the intermediate Compounds A and B aresaturated in the 1,2; 4,5; and 6,7 positions (such intermediates beingpreferred), the resulting inactive CompoundsC can be converted tophysiologically active steroids by introducing a double-bond in the 4,5-position. This may be done by: (l) reacting Compounds C, wherein thesteroid nucleus is saturated and of the pregnane configuration, withapproximately one mole of bromine permole of steroid, thereby formingCompounds D containing a 4fl-bromo substituent, and dehydrobrominatingas by treatment with an alkali metal halide (such as an alkali metalchloride, as exemplified by lithium chloride) or with a hydrazinederivative (e.g. dinitrophenylhydrazine or semicarbazide) to form thecorresponding hydrazone or semicarbazone, followed by decomposition ofthe latter with a keto acid (e.g. pyruvic acid) to prepare a A-pregnene, Compounds E, which correspond to Compounds C wherein the 4,5position is double-bonded; or (2) reacting Compounds C, wherein thesteroid nucleus is saturated and may be either of the pregnane orallopregnane configuration, with two moles of bromine per mole ofsteroid, thereby forming Compounds F containing 2,4-dibromo substituent(20:,40: if Compounds C are allopregnanes and 25,45 if Compounds C arepregnanes), and dehydrobrominating by treatment with an organic basesuch as pyridine or collidine, to prepare a mixture (which is separableby chromatography) of d -pregnadiene, Compounds G, and A pregnadiene,These derivatives correspond to Coma wherein the 1,2- and 6,7-positionsare saturated or double-bonded; R, R, X, Y, and Z are as hereinbeforedefined; and individually R is hydrogen, R" is hydroxy, and together R"and R represent keto or ketalized keto, are physiologically activesteroids which possess glucocorticoid as well as mineralocorticoidactivity. Thus, the new steroids of this invention can be administeredinstead of, and in the same manner as, cortisone or hydrocortisone inthe treatment of rheumatoid arthritis and dermatomyositis, or in thesame manner as desoxycorticosterone in the treatment of Addisons diseaseor adrenal iusuficiencies. The dosage for such administration is, ofcourse, dependent on the relative activity of the compound; thus, wherethe steroid derivative has approximately the same activity or"cortisone, the dosage of the former to be employed should beapproximately equal to the employed dosage of the latter. ThelZa-bromo-l 1- keto-steroids of this invention are of further use asintermediates in the preparation of the corresponding 12- debromoderivatives, to which they are converted by treatment either withbromine in acetic acid or chromous chloride.

For the purpose of illustrating the preferred process of this invention,reference is made to the following schematic analysis employing A-pregnene-3,20dione as the starting material:

a C=O CH OONHBl CH CH J BI: LiCl O: 0

in (III) X=Cl (V) X=Cl (IV) X=F (VI) X=F CH CH3 The following examplesare illustrative of the invention (all temperatures being incentigrade):

EXAMPLE 1 IZa-Bromopregnane-l 1,8-0l-3,20-Di0ne (I To a solution of 300mg. of A -pregnene-3,20-dione in 40 ml. of pure dioxane and 4 ml. ofwater is added 240 mg. of N-bromoacetamide and shortly thereafter 2.0ml. of 1 N aqueous perchloric acid. After 25 minutes at room temperature5% aqueous sodium sulfite is added to destroy the excessN-bromoacetamide and shortly thereafter 75 ml. of chloroform. Afterseparating oi? the aqueous layer the chloroform layer is washed withdilute sodium bicarbonate, and water, and dried over sodium sulfate.After evaporation of the solvent in vacuo, the residue is leached withethyl acetate leaving about 262 mg. of crystalline material, melting atabout 228-230 (dec.). This material on recrystallization fromtetrahydrofurane-hexane gives pure 12u-bromopregnane-1 lfiol-3,20-dione,having the following properties: M.P. about 251252 (dec.); +76 (c., 0.37in dioxane).

Analysis.-Calcd. for C H O Br (411.38): C, 61.31; H, 7.60; Br, 19.43.Found: C, 61.70; H, 7.19; Br. 19.73.

This steroid has previously been described by Hegner and Reichstein[Helv. Chim. Acta 26, 721 (1943)]. In a similar manner, A-pregnene-21-ol-3,20-dione 2l-acetate, A -pregnadiene-3,20-dione and A-pregnadiene-21-ol- 3,20-dione 21-acetate can be converted to12a-bromopregnane-l1,8,21-di0l-3,20-dione 21-acetate, 12Ot-bl'OmO-Apregnane-l1 8-ol-3,20-dione and 12a-bromo-A-pregnenellfl,2l-diol-3,20-dione 21-acetate, respectively.

EXAMPLE 2 1 1 3,1 ZB-Epoxy-Pregnane-3,20-Di0ne (II) To a solution of 271mg. of 12u-bromopregnane-11,8-01- 3,20-dione in 24 ml. of methanol isadded 220 mg. of potassium carbonate in 1.2 ml. of water. The mixture isagitated at room temperature for 18 hours, after which the methanol isremoved in vacuo. Extraction of the residual mixture with etherfurnishes about 247 mg. of crystalline material which is recrystallizedfrom acetonehexane. Pure 11,6,1ZB-epoxy-pregnane-B,20-dione has thefollowing properties: M.P. about 139-140"; [01],; +89 (c., 0.38 inchlf.);

Analysis.Calcd. for C H O (330.45): C, 76.32; H, 9.15. Found: C, 76.15;H, 8.90.

Similarly, 12cc bromopregnane-l1,8,21-di0l-3,20-dione 2l-acetate,12a-brorno-A -pregnene-l lfi-o1-3,20-dione and 12u-brom0-A-pregnene-1lti,2l-diol-3,20-dione ZI-acetate, can be converted tol113,IZB-epoxy-pregnane-Zll-3,20- dione ill-acetate, 11B,l2B-epoxy-A-pregnene 3,20-dione and 11 8,12,3-epoxy-A -pregnene-21'ol-3,20'dione21-acetate, respectively.

EXAMPLE 3 12u-Chloropregnane-I1fl-ol-3,20-Dione (-III To a solution of63 mg. of 11fi,12;8-epoXy-pregnane- 3,20-dione in 10 ml. of pure dioxaneis added 2.5 ml. of 2.5 N-aqueous hydrochloric acid. The mixtureisstirred at room temperature for 1 hour after which 30 ml. of chloroformis added. Separation of the layers followed by washing of thechloroform-dioxane phase with dilute sodium bicarbonate solution andwith water and subsequent drying over sodium sulfate furnishes afterevaporation of the solvent in vacuo about 65 mg. of essentially pure12achloropregnane-l1B-ol-3,20-dione; M.P. about 241-244 (dec.). Theanalytically pure substance has the following properties: M.P. about246-248" (dec.); [M +80 (0., 0.31 in chlf.);

Am? 2.96;; (OH), 5.83 (8-keto), 5.95 (20-keto) Analysis.--.Calcd. for CH O Cl (366.92): C, 68.74; H, 8.52; Cl, 9.66. Found: C, 69.16; H, 8.50;Cl 9.36.

EXAMPLE 4 1'2a-Fluor0pregnane-1 1 {3-01-3 ,ZO-Dione (IV) To a mixture of1 ml. of methanol and 1.5 ml. of liquid hydrogen fluoride is added at-76", 75 mg. of 115,125- epoxy-p'regnane-ii,20-dione. The resultingsolution is allowed to warm up slowly to and at that point another 1 ml.of hydrogen fluoride is added. The mixture is then keptat roomtemperature for hours during which time itassumes' a deep red color.Chloroformis added, the resulting solution is immersed into an ice-bathand the hydroge'n fluoride neutralized; by the addition of a suspension'of so dium bicarbonate in water. Extraction of the chloroform solutionwith water gives after drying over sodium sulfateand evaporation of thesolvent in vacuo about 84 mg. of an amorphous residue. The'latter ischromatographed on 2 g. of sulfuric acid-washed alumina and the columneluted with 200 ml. of benzene-hexane lil 3 00 ml. benzene-hexane 3:1and 250 ml. of benzene. The last two eluants furnishes12a-lluoropregnane-lidol-3,20- dione which after recrystallization fromethyl acetatehexane has the following properties: M.P. about 186-187;'[4]D230[9%]54623 0 Q 1);

If '113,1ZB-epoxy-pregnane-Z1-ol-3,2Q dione 2l-acetate, 11,3,12B-epoxy-A-pregnene-3,20fdione, or l1p,12}3-e'poxy- A -pregnene-2l-ol-3,20-dioneZl-acetate is substituted for 95,1lfi-epoxy-pregnane-S,ZO-dione in theprocedure of Example 3 or 4, the corresponding IZa-ChlOIQ-llB-hY- droxyand 12u-fluoro-11B-hydroxy steroid derivatives are prepared,respectively.

To a solutionof 50 mg.,of 12a-chloropregnane- 1ltkol- '-3,20-dionein,1OIml. of glacialacetic acid is added a drop of hydrogen bromideinacetieaeid and then of 25 mg. of bromine in 1 mLof max.

Ydropwise a solution glacial acetic acid. After addition of 30mg..ofsolid sodium acetate the solvent is removed in vacuo and the residuetaken up in chloroform. The resulting chloroform solution 'is washedwith dilutesodiurn bicarbonate and water and after drying over sodiumsulfate evaporated to dryness. The crys tallineresidue (about 75mg.)consists of essentially pure l2b;-chloro-4B-bromopregnane-11;8-ol-3,20-dione, M.P. about l84. l86 (dec.); [01.]; ((2., 0.5 in01315.);

R 2.95;; (OH), 5.78;; 4-bromo-3-ketone), 5.92;;

max.

(ZO-ketone) EXAMPLE 6 45-Brom0-12a-Fiuoropregnane-I1B-0l-3,20-Di0ne (VI12u-Chloro-M-Pregnane-l1.;8a0l-3,20!Di0ne [1 Zen-Chloro- 1 1B-Hydmxypmgestemne] (VII) A solution of 73 mg. ofi2a-chloro-4B-bromopregnane- 11B-o1-3,20-dione and mg. of anhydrouslithium chloride in 5 ml. of redistilled di-methylformamide is heated at100 under nitrogen for 2 /2 hours. The solution is then diluted withchloroform and extracted with water, dilute sodium bicarbonate solutionand again with water. After drying over sodium sulfate the solvent isevaporated in vacuo leaving a crystalline residue (about 47 mg.) ofessentially pure 12cc chloro A pregnene-1lfi-ol-3,20- dione. The latteris obtained in pure form after recrystallization from acetone-hexaneandhas the, following properties: M.P. about 218-220", [u] +:146 (0., 0.46in .ch1f.); 7

12a. chloro A pregnene 11fl ol-3,20-dionepossesses about one-half theactivity of cortisone acetate in the rat liverglycogen assay. A

EXAMPLE 8 IZwFIuOrO-M-PregHene-I 1 [3-02. 3 ,2 O-Dione ['1 Zea-.F luoro-11 fl-Hydroxyprogestrone] VII I EXAMPLE 9 IZa-Chloro-A -Pregnene3J1,20-Trione [1 Zea-Chloro- 1 1 -Ket0pr0gester0ne] (IX) To a solutionof 10 mg. of lZa-chloro-M-pregnenel1;9-ol-3,20-dione in 1 ml. of glacialacetic acid is added a solution of 3.5 mg. of chromium trioxide in 1 ml.of glacial acetic acid. Ten minutes later the chromium trioxide isdestroyed by the addition of A1 ml. of ethanol and the solutionconcentrated to asyrup in vacuo. The residue is taken up in chloroformand extracted with water, dilutesodium bicarbonate and again with water.After drying over sodium sulfate the chloroform is evaporated in vacuoand the semi-crystalline residue chromatographed on200 mg. of sulfuricacid-washed alumina. Elution of the column with a mixture containing 25%benzene and 75% hexane furnishes crystalline material which onrecrystallization from 95% ethanol melts at about 170-173";

A315,; 236 m (=9,000) 12a.-chloro-A -pregnene-3,'11,20-trione possessesabout /2 the activity of cortisone acetate in the rat liver glycogenassay.

EXAMPLE 10 12a-Flu0r0-A -Pregnene-3,1 1,20-Tri0ne [1 Zea-Fluore- 1 1-Ketoprogester0ne] (X) and 12a-fluorocorticosterone ZI-acetate can beoxidized to 12a.-chloro-1l-dehydrocorticosterone acetate and12afluoro-ll-dehydrocorticosterone acetate, respectively.

The invention may be otherwise embodied within the scope of the appendedclaim.

We claim:

1 1,6, lZB-epoxypregnane-B,ZO-dione.

References Cited in the file of this patent UNITED STATES PATENTSRechstein May 29, 1951 Wettstein et a1 Feb. 19, 1957 OTHER REFERENCES

